A phase I study of intravenous (IV) milataxel in combination with carboplatin in adult patients with advanced malignant solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13525-e13525
Author(s):  
W. A. Flood ◽  
L. D. Lewis
Keyword(s):  
Solid Tumors ◽  
Malignant Tumors ◽  
Response Duration ◽  
Median Number ◽  
Primary Objective ◽  
Fixed Dose ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Ecog Ps

e13525 Background: Milataxel (MXL) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The primary objective of this study was to determine the MTD when MXL was given intravenously in combination with a fixed dose (AUC=6) of carboplatin (C) every 21 days in subjects with advanced malignant solid tumors. Secondary objectives were to (i) assess the safety and tolerability of the combination (ii) define the pharmacokinetics of MXL and C when given in combination (iii) obtain preliminary information on the antitumor activity of MXL+C. Methods: Key subject eligibility criteria included: adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. PK data was obtained on day 1 for MXL and both free and bound platinum. Results: 11 pts (median age 60; 2 F,9 M) were treated. MXL was dose escalated in three cohorts (15, 20 and 25 mg/m2). Three patients were treated at 15 mg/m2 of MXL without a DLT. At the 25 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose (1 pt - grade 3 febrile neutropenia, grade 4 thrombocytopenia; 1 pt - grade 4 ANC, grade 4 thrombocytopenia). At the 20 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose with both pts having grade 4 ANC. The MTD and the recommended Phase II dose of MXL was 15 mg/m2 plus C (AUC= 6). The median number of cycles administered was 3 (range 1–16). The most frequent grade 3 or 4 treatment emergent adverse events were neutropenia (82%), leukopenia (55%), pancytopenia (27%), asthenia (18%), generalized edema (18%), thrombocytopenia (18%), anemia (18%), confusion (18%), and dyspnea (18%). One pt in the MTD cohort with cholangiocarcinoma had a PR. This patient received 16 cycles of therapy and had a response duration of 378 days and a TTP of 406 days. PK data (n=9) showed the elimination half-life of MXL ranged from 26 to 110 h, and that for free and total platinum were as would be predicted for C monotherapy. Conclusions: The MTD of MXL was 15 mg/m2 IV per three week cycle when combined with carboplatin (AUC= 6). One patient with a cholangiocarcinoma had a sustained PR for 378 days. No significant financial relationships to disclose.

Phase I study of intravenous (IV) milataxel in adult patients with advanced malignant tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2037-2037 ◽  
Author(s):  
E. Bourbouloux ◽  
M. Campone ◽  
J. B. Vermorken ◽  
M. Martin ◽  
C. Sessa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dose Escalation ◽  
Malignant Tumors ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Eligibility Criteria ◽  
Ecog Ps

2037 Background: M (TL139, MAC-321) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The maximum tolerated dose (MTD) when given IV every 3 weeks was 35 mg/m2. The current study was designed to determine if the dose intensity of M could be increased by a weekly IV schedule. Methods: The primary objective of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD) for phase II. Secondary objectives were pharmacokinetic (PK)/pharmacodynamic (PD) parameters of M given IV weekly and a preliminary estimate of efficacy in an expanded cohort at the RD. Key pt eligibility criteria included in adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. Patients were not allowed concurrent strong inhibitors of cytochrome p450 3A4. Dose escalation was based on Fibonacci method. At the RD, additional pts with tumors that typically respond to taxane treatment were added. PK data were obtained on day 1 and 15. Results: A total of 32 pts were treated, 15 (6 females, 9 males) in the dose escalation part and 17 (15 females, 2 males) in the MTD confirmation part. The median number of doses was 11 (range 1–18). In the dose escalation phase, 3, 4, and 3 pts were treated at 8, 12, and 16 mg/m2 IV weekly without DLT. At 20 mg/m2, 2 of 5 pts developed DLT (1 pt - myalgia and neuropathy, 1 pt grade 4 neutropenia > 5 days in duration). The RD was 16 mg/m2 weekly. 17 more pts were treated at the RD. The most frequent grade 3 or 4 adverse events were asthenia (19%), nausea (9%), parethesia (9%) and neuropathy (9%). Of the 10 pts with breast cancer who were evaluable for response, one had a PR. Another breast cancer pt with a PR was a protocol violation and was not evaluable. In 20 pts at the MTD, the Tmax was 4 hr, the Cmax was 51.97 ng/mL, AUC 2711 ng*hr/mL, and the Vss was 1496 L/m2. Conclusions: Milataxel had an RD of 16 mg/m2 IV per week. Objective responses were observed in pts with metastatic breast cancer. No significant financial relationships to disclose.

Phase II study of talabostat and rituximab in fludarabine/rituximab-resistant or refractory patients with CLL

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6598-6598 ◽  
Author(s):  
K. D. Khan ◽  
S. O’Brien ◽  
K. R. Rai ◽  
J. R. Brown ◽  
C. Abboud ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Stage Iv ◽  
Response Duration ◽  
Median Number ◽  
Open Label ◽  
Eligibility Criteria ◽  
Primary Resistance ◽  
Molecule Inhibitor ◽  
Grade 3 ◽  
Ecog Ps

6598 Background: Talabostat (TAL) is an orally administered small molecule inhibitor of dipeptidyl peptidases such as CD26 and fibroblast activation protein (FAP) in bone marrow, lymph nodes, and stroma of solid tumors, and TAL induces cytokine and chemokines in lymph nodes and spleen. TAL enhances the activity of rituximab (RTX) in a mouse model of lymphoma. This study evaluates the efficacy of TAL + RTX in patients with advanced CLL who failed fludarabine (FLU) and/or RTX. Methods: Single-arm, open-label study of RTX 375mg/m2 weekly × 4 weeks, and TAL-300mcg BID for 6 days following each RTX infusion for a tx course of 28 days. Additional courses permitted depending on tolerability. Eligibility criteria include ECOG PS 0–2, CD20+ B-CLL, Rai Stage III/IV or Rai I/II with marked lymphadenopathy, no CNS metastases, and primary resistance or PD following FLU and/or RTX. Primary endpoint is response rate per NCI-WG criteria. Secondary endpoints include response duration, PFS, and survival. Results: 40 patients (32 men, 8 women), median age 64.0 (range 42–83) have entered the study. Most (85%) are caucasian, and 78% of patients are Rai Stage IV. Mean serum B2 microglobulin is 6.5mg/L. The median number of prior regimens is 4 (range 1 to 10); 78% of patients received prior RTX and 33% prior alemtuzumab. Partial response (PR) has been reported in 8/36 evaluable patients (22%), 6 of whom had failed RTX; 3 of these patients had also failed alemtuzumab. Response duration currently ranges from 2 to 10 months (median 5.0 months). Most toxicities are Grade 1 or 2, and include nausea, fever (28% each), and edema (25%). Fever with associated Grade 3 or 4 neutropenia is reported in 2 and 1 patient, respectively. Other Grade 3 AEs include dyspnea (n=3), fatigue (n=2), and aspergillus pneumonia and a dermal fungal infection in 1 patient each. Grade 4 AEs are thrombocytopenia, hypoglycemia, and pulmonary embolism in 1 patient each. 4 patients died due to CLL (2 due to PD) or related complications (PE or MRSA pneumonia, 1 each). Conclusions: TAL + RTX shows promising activity in CLL patients with advanced disease who failed FLU and/or RTX. AEs are similar to those seen with RTX, with the exception of edema in 25% of patients. Updated results, including median PFS and survival will be presented at the annual meeting. [Table: see text]

Cabazitaxel plus cisplatin coadministration and drug-interaction study in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15116-e15116
Author(s):  
Alain C. Mita ◽  
Shankar Sundaram ◽  
John Sarantopoulos ◽  
Monica M. Mita ◽  
Alex R. Lane ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Primary Tumors ◽  
Grade 3 ◽  
Ecog Ps ◽  
Cyp3a Inhibitor

e15116 Background: Cabazitaxel (Cbz) is a novel taxane with in vivo efficacy in taxane-sensitive and -resistant tumors. Therapeutic synergism of Cbz/cisplatin (Cis) has been shown in tumor-bearing mice. Since Cbz is primarily metabolized by CYP3A, drug interactions may occur with modulators of CYP3A. Methods: The primary objective of part 1 of this phase I study (NCT00925743) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives included safety, pharmacokinetics (PK) and efficacy. The objective of part 2 was to assess efficacy at the MTD. The effect of the antiemetic aprepitant (a moderate CYP3A inhibitor) on the PK of Cbz was also examined. Eligible patients (pts) had ECOG PS ≤ 1 and confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation at a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (n = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). Of 6 evaluable pts, 2 had a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed; 18 pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all grades/grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of grade 3–4 neutropenia was 78%; 1 pt had febrile neutropenia. The combined PK profile of Cbz/Cis did not appear to differ vs those of the single agents. The ratio of Cbz clearance with vs without aprepitant co-administration was 0.81 (90% CI 0.36–1.85). Stable disease was seen in 11 pts; 1 pt (prostate carcinoma) had an unconfirmed partial response. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with a platinum/taxane combination. No PK interactions between Cis and Cbz were seen; aprepitant did not appear to alter the PK of Cbz.

NCIC IND.190: A phase I trial of MK-0646 in combination with cisplatin and etoposide in extensive-stage small cell lung cancer (ES SCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7093-7093
Author(s):  
Peter Michael Ellis ◽  
Frances A. Shepherd ◽  
Scott Andrew Laurie ◽  
Glenwood D. Goss ◽  
Martin Sebastian Olivo ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Serum Levels ◽  
Median Number ◽  
Neutropenic Sepsis ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Number Of Treatment ◽  
Ecog Ps ◽  
Cell Growth And Proliferation

7093 Background: Increased serum levels of insulin like growth factor (IGF), plus overexpression of the IGF-receptor (IGFR) are implicated in SCLC cell growth and proliferation, making suppression of the IGFR a potential therapeutic target. MK-0646 is a monoclonal antibody directed against the IGFR. The aim of this study was to determine the recommended phase II dose (RP2D) of cisplatin, etoposide plus MK-0646. Methods: We conducted a phase I study of two dose levels of MK-0646 (DL1 5mg/kg, DL2 10mg/kg IV weekly) in combination with cisplatin (25mg/m2) and etoposide (100mg/m2) IV D1-3, q21d, for patients with chemotherapy-naive ES SCLC, PS 0-2. Patients with treated stable brain metastases were eligible. Patients completing 4-6 cycles of combination therapy could continue single agent MK-0646 until disease progression. Primary outcome was determination of the RP2D. Secondary outcomes included ORR (RECIST 1.1), and toxicity (CTCAEv3). Results: A total of 12 patients were treated (DL1 – 3, DL2 – 9). The median age was 63 years (48-70), with 6 males and 6 females. Most subjects were good ECOG PS (PS 1 – 8, PS 2 – 4) and had 4 or more sites of disease (n=8). No DLTs were observed in DL1 or DL2. In an expanded DL2 cohort, 1 patient died from neutropenic sepsis during cycle 1. The median number of treatment cycles of chemotherapy was 4 (DL1) or 5 (DL2) and MK-0646 was 6 (DL1&2). Dose delays were observed for chemotherapy (DL1 - 2, DL2 – 6) and MK-0646 (DL1 – 3, DL2 – 7). The confirmed ORR was 72.7% (PR 8, SD 2, PD 1, non-evaluable 1). Grade ≥3 toxicities (any cycle) occurring in more than 1 patient included: neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia (17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 hyperglycemia was observed in 1 of 3 (DL1) and 5 of 9 (DL2). Eight SAEs were observed in 3 patients (thrombosis, febrile neutropenia, infection, syncope, fatigue 2, dyspnea, back pain). Conclusions: MK-0646 can be combined at full dose with standard doses of cisplatin and etoposide (25mg/m2 and 100mg/m2 D1-3) with a RP2D of MK-0646 10mg/kg/week. The observed toxicities are consistent with that expected from cisplatin and etoposide except for hyperglycemia, which appears dose dependent.

A phase I study of APL-501, an anti-PD-1 antibody, in patients with recurrent or advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15125-e15125
Author(s):  
Mark Voskoboynik ◽  
Gary Edward Richardson ◽  
Linda R. Mileshkin ◽  
Catriona M. McNeil ◽  
Lisa Horvath ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Median Number ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Grade 3 ◽  
Refractory Solid Tumor ◽  
Ecog Ps

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

Phase II study of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14070-14070 ◽  
Author(s):  
K. Sudo ◽  
T. Yamaguchi ◽  
T. Ishihara ◽  
K. Nakamura ◽  
H. Saisho
Keyword(s):  
Pancreatic Carcinoma ◽  
Performance Status ◽  
Rest Period ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
Advanced Pancreatic Carcinoma ◽  
Grade 3 ◽  
Ecog Ps

14070 Background: S-1 is an oral fluoropyrimidine derivative with reported response rate of 21.1∼37.5% for advanced pancreatic carcinoma (Ueno, Oncology 2005; Furuse, ASCO 2005). The primary objective of this study was to assess the efficacy and safety of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma. Methods: Patients with histologically or cytologically proven, metastatic pancreatic carcinoma who had failed prior chemotherapy with gemcitabine were eligible for this study. Other eligibility criteria included an ECOG performance status (PS) of 2 or less; an age of at least 20 years; adequate organ function; and written informed consent. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks until disease progression. Results: Seventeen patients were enrolled with the following characteristics: median age 67 (range 40–75); male/female = 9/8; ECOG PS 0/1/2 = 1/8/8. All patients were included in analysis. Treatment was generally well tolerated and no life threatening toxicity was observed. Grade 3–4 toxicities were anorexia (17.6%) and fatigue (5.9%). Common grade 1–2 toxicities were anorexia (35.3%), anemia (35.3%), leukocytopenia (29.4%) and diarrhea (23.5%). Three patients were discontinued S-1 because of toxicities. Out of the 17 eligible patients, 3 patients (17.6%) achieved a partial response and 5 patients (29.4%) had stable disease. A marked decrease (≥50%) in tumor markers was observed in 5 (29.4%) of the patients. (CA 19–9 in 3 patients, CEA in 1 patient, DUPAN-2 in 1 patient) The median progression-free survival and the median survival time from the date of initiation of S-1 were 4.1 months (95% CI, 2.0 to 6.2 months) and 5.7 months (95% CI, 2.6 to 8.7 months), respectively. Conclusions: S-1 is well tolerated and active in patients with gemcitabine resistant advanced pancreatic carcinoma. Further investigation of this treatment appears warranted. No significant financial relationships to disclose.

Liver resectability following mFOLFOX6 with bevacizumab as the first-line treatment of unresectable liver limited metastases from colorectal cancer in Japanese patients (KSCC 0802).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 666-666 ◽  
Author(s):  
Hironori Samura ◽  
Toru Beppu ◽  
Yasunori Emi ◽  
Yoshihiro Kakeji ◽  
Hiroshi Saeki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Japanese Patients ◽  
Median Number ◽  
Line Treatment ◽  
First Line ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Multi Center Study ◽  
Ecog Ps ◽  
First Line Treatment

666 Background: There is no data concerning liver resectability following mFOLFOX6 with bevacizumab as the first-line treatment of unresectable liver limited metastases from colorectal cancer by prospective, multi-center study in Japan. The Kyushu Study group of Clinical Cancer (KSCC) conducted a phase II trial in this setting. Methods: Eligibility criteria included unresectable liver limited metastases from histologically confirmed advanced colorectal cancer, ECOG PS 0-1 and adequate general condition. Patients (pts) received 6 cycles of mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2 d1 followed by 400 mg/m2 bolus 5-FU and a 46-hr 2,400 mg/m2 5-FU infusion every 2 weeks) with bevacizumab (5mg/kg) followed by evaluating the liver resectability. (UMIN000001308) Results: Of the 40 pts enrolled from Sept. 9 2008 to Aug. 10 2010; M/F, 29/11; Median age, 63 years (range 37-74); ECOG PS 0/1, 38/2. The median number of administration cycles was 6 (range, 1–7). Response for CR, PR, SD, PD and NE were 0 (0 %), 12 (30.0 %), 22 (55.0%), 3 (7.5%) and 3 (7.5%), respectively. An overall response rate was 30.0% (95% CI: 16.6 % – 46.5 %). The grade 3-4 adverse events were; leukopenia (10%), neutropenia (32.5%), febrile neutropenia (5%), fatigue (2.5%), appetite loss (2.5%), diarrhea (2.5%), mucositis (2.5%), high AST (2.5%) and ileus (2.5%). The number of cases to intent operation was 17 (42.5%), the liver resectability was 16/40 (40.0 %). The number of R0 cases was 10 pts (25.0%, 95% CI; 12.7 - 41.2 %). Conclusions: mFOLFOX6 with bevacizumab regimen is safe and effective for unresectable liver limited metastases from colorectal cancer, and might be to lead the high liver resectability.

Phase I multicenter, open-label study to establish the maximum tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin combination in patients (pts) with metastatic colorectal cancer (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 816-816 ◽  
Author(s):  
Antoine Hollebecque ◽  
Aitana Calvo ◽  
Thierry Andre ◽  
Guillem Argiles ◽  
Andres Cervantes ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Published Data ◽  
Open Label ◽  
Treatment Delays ◽  
Open Label Study ◽  
Grade 3 ◽  
Ecog Ps

816 Background: Preclinical evidence suggests improved efficacy when combining trifluridine/tipiracil with oxaliplatin compared to each monotherapy (Nukatsuka, 2015). The primary objective was to determine the MTD and the safety profile of the doublet among mCRC pts who have progressed after at least one prior line of treatment. Methods: Using a 3+3 design, eligible pts received escalating trifluridine/tipiracil doses from 25, 30 to 35 mg/m² bid, days 1–5 q14, together with a fixed dose of oxaliplatin 85 mg/m² (day 1). An intermediate cohort with a lower dose of oxaliplatin (65 mg/m²) plus 35 mg/m² of trifluridine/tipiracil was also tested. Results: Fifteen of 17 enrolled pts were evaluable for DLTs. Median age was 61 years (range 32-74), 11 and 6 pts had an ECOG PS of 0 and 1, respectively; 76% received ≥2 lines including for 10 pts previous line with oxaliplatin. Pts received a median of four cycles (range 1–23). The MTD was defined at the maximal planned dose: trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m². Combination was well tolerated and only one DLT was observed (grade 3 febrile neutropenia). The most common ( > 20%) non-hematologic adverse drug reactions (ADRs) included nausea, asthenia, vomiting, diarrhea and decreased appetite. Moderate-to-severe neutropenia occurred in 5 pts and thrombocytopenia in 4 pts (all grade 1); 1 pt experienced a grade 4 anemia at Cycle 4. Oxaliplatin-related neurotoxicity grade ≥2 was observed in 2 pts. ADRs were manageable with basic supportive care, with treatment delays or temporary interruptions. Best overall response includes partial response (n = 1, unconfirmed), stable disease (n = 7). Conclusions: At the MTD (trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m²), incidence and severity of bone marrow suppression as well as gastrointestinal toxicities were similar to previously published data. A cohort of 6 additional pts will confirm the MTD. An expansion part combining the doublet with either nivolumab or bevacizumab evaluating the safety and preliminary antitumor activity of each triplet will start soon. Clinical trial information: NCT02848443.

scholarly journals O83 Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A2.1-A2
Author(s):  
Ronnie Shapira-Frommer ◽  
Marloes GJ van Dongen ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
Fang Liu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Grade 5 ◽  
Crossover Phase ◽  
Grade 3 ◽  
Ecog Ps

BackgroundMK-5890 is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses. This first-in-human phase 1 study of MK-5890 evaluated the safety and efficacy of escalating doses of MK-5890 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.MethodsKey eligibility criteria included histologically or cytologically confirmed advanced solid tumor, measurable disease by RECIST v1.1, and ECOG PS ≤1. MK-5890 was tested alone (dose range, 2-700 mg) or with pembrolizumab (fixed dose, 200 mg). Patients with disease progression following MK-5890 monotherapy were eligible to cross over to combination treatment. The primary objective was safety and tolerability. Objective response rate by investigator per RECIST v1.1 was also evaluated. The database cutoff for this analysis was May 30, 2019.ResultsOf 44 patients enrolled, 25 received MK-5890 and 19 received MK-5890 plus pembrolizumab; their median age was 59.0 years, 61.4% were female, 47.7% had ECOG PS 1, and 13.6% previously received immune checkpoint inhibitor therapy. In the initial phase, dose-limiting toxicities (DLTs) were reported in 3 patients receiving MK-5890 and 1 patient receiving MK-5890 plus pembrolizumab; all DLTs were associated with infusion-related adverse events. Maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) were reported in 40 patients (90.9%): 22 patients (88.0%) receiving MK-5890 and 18 patients (94.7%) receiving MK-5890 plus pembrolizumab. The most common TRAEs were fatigue (28.0%) and infusion-related reactions (28.0%) with MK-5890 and fatigue (36.8%) and pruritus (31.6%) with MK-5809 plus pembrolizumab. Grade 3-4 TRAEs were reported in 10 patients (22.7%): 6 patients (24.0%) receiving MK-5890 and 4 patients (21.1%) receiving MK-5890 plus pembrolizumab; no grade 5 events were observed. One patient (4.0%) achieved a partial response (PR) with MK-5890 and 1 patient (5.3%) achieved a PR with MK-5890 plus pembrolizumab. Fourteen patients entered the crossover phase to receive MK-5890 plus pembrolizumab. In the crossover phase, no DLTs were reported. TRAEs were reported in 12 patients (85.7%); the most common were pruritus (21.4%), rash (21.4%), and headache (14.3%). One patient (7.1%) reported grade 3-4 TRAEs of increased amylase and increased lipase; no grade 5 events were observed. Two patients (14.3%) achieved a complete response and 2 patients (14.3%) achieved a PR.ConclusionsTreatment with MK-5890, alone and in combination with pembrolizumab, demonstrated an acceptable safety profile. Early antitumor activity was observed in patients with advanced solid tumors in both monotherapy and combination therapy arms.

A phase I trial combining motexafin gadolinium (MGd) with docetaxel in the treatment of advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13115-13115
Author(s):  
K. J. Pandya ◽  
S. Phan
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Foot Drop ◽  
Advanced Solid Tumors ◽  
Motexafin Gadolinium ◽  
Grade 3

13115 Background: MGd is a novel therapeutic agent that concentrates in tumors and generates reactive oxygen species. Pre-clinical models show that MGd enhances in tumors the cytotoxic activity of selected chemotherapies, including taxanes. This phase I trial studied the combination of MGd and docetaxel. Methods: Patients (pts) with advanced solid tumors, adequate bone marrow, hepatic and renal function were eligible. Cohorts of 3 pts were treated with MGd starting at 2.5 mg/kg followed 30 minutes later by docetaxel 75 mg/m2. Treatments were repeated q3wks. The primary objective was to determine the maximum tolerated dose (MTD) of MGd in combination with docetaxel on this schedule and to determine the dose limiting toxicities (DLT). The secondary objective was to evaluate the response rate. MGd dose was escalated in successive cohorts while docetaxel dose remained fixed. Results: Sixteen pts were entered (9 males, 7 females) at MGd dose of 2.5 to 10 mg/kg. The median age was 60.5 yrs (range 35 -75). ECOG PS0 (4), 1 (14). Diagnoses included prostate (1); ovarian (2); breast (2) and non-small cell lung (NSCLC) (11). Median number of prior chemotherapy regimens: 2 (range 1–14), 7 pts had previously received a taxane: paclitaxel 5, docetaxel 2. Reported toxicities (all grades) include urine discoloration from excretion of MGd (68%), fatigue (87%), diarrhea (81%) and nausea (56%), Grade 3 neutropenia (37.5%) febrile neutropenia (6%), neuropathy (foot drop) was seen in 1 patient, therefore additional pts were entered (4 registered, but 1 never treated) at 10 mg/kg dose. Recurrence of prior radiation esophagitis was seen in 1 pt therefore it was felt that DLT was reached and study was closed. Responses are as follows: PR by CT in 1 breast and 4 NSCLC, and by PSA in 1 prostate; SD by CT in 1 breast and 2 NSCLC. Conclusion: MGd 10 mg/kg in combination with docetaxel 75 mg/m2 is feasible and did not increase docetaxel toxicity while showing promising responses. Phase II study of this combination is underway in NSCLC. [Table: see text]

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